The mutant mouse, spastic, specifically binds no, or very little strychnine in spinal cord, brain stem, and midbrain, suggesting a marked deficit in glycine receptors. No changes are seen in GABA, benzodiazepine, or muscarinic receptors, suggesting that the deficit is psecific to glycine receptors. Experiments demonstrating this finding were initiated after careful electrophysiological analysis of the spastic movement disorder and comparison with partially strychninzed normal animals (Heller and Hallett, in press). This may be the first example of a mammalian central nervous system neurological disease mediated by a genetically determined deficit of a single neurotransmitter receptor. This proposal is designed to 1) establsh the relationship between the neurological syndrome of the spastic mouse and the specific deficit in glycine receptors, 2) investigate the relationship between the strychnine binding site and the postsynaptic glycine receptor, 3) attempt to determine if this is the primary defect of the mutation, 4) use the spastic mouse as a model to understand the role of glycine inhibition in mammalian CNS function, 5) examine potential compensatory mechanisms utilized by the CNS and 6) hopefully establish the methodology for the investigation of the spastic mutant as an example for further searches for neurological diseases caused by deficits in specific synaptic function. Specific investigations proposed include further characterization of the strychnine receptor in the spastic mutant, determination fregional and developmental characteristics of the deficit, investigation of a possible gene dosage effect in the heterozygote, and a validation of strychnine binding as a measure of glycine receptors. Studies of other aspects of the glycine inhibitory system (content, metabolism, uptake, and release) will also be performed. PReliminary studies indicating that the deficit is specific for the glycine system and that the spastic spinal cord is anatomically normal will be expanded. Spinal cord neurons from spastic animals will be grown in cell culture and studied to determine if they also demonstrate an absence of strychnine binding, show the expected deficit in physiological response to glycine using intracellular recordings and glycine miniperfusion, show any electrophysiological abnormalities unrelated to the glycine syste, or develop any compensatory changes in GABA inhibitory input.